Pimobendan is a well-known compound for the treatment of congestive heart failure (CHF) originating for example from dilated cardiomyopathy (DCM) or decompensated endocardiosis (DCE) in animals, especially dogs (WO 2005/092343). Pimobendan is also approved as a drug product for cardiovascular treatment of humans.
Pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) is disclosed in EP B-008 391, herein incorporated by reference in its entirety, and having the formula:

As already was described in EP A-439 030 and WO 2005/08467, pimobendan drug substance is insoluble in water, 1 g substance is soluble in more than 10000 ml. At pH 7 the solubility of pimobendan is about 0.1 mg per 100 ml.
The substance is administered by the oral route twice daily. Yet no liquid preparation comprising pimobendan is available. In order to achieve an immediate onset of action for all the innovative indications mentioned above, an injectable solution for parenteral administration by the i.v. and/or s.c. route is obligatory. An aqueous formulation is required to administer a drug product by the i.v./s.c. route to either humans or animals, formulations with a non-aqueous solvent are neither acceptable nor state of the art due to the risk of severe tolerance problems.
Solubility in aqueous solutions is depending on the pH. The solubility of pimobendan is significantly higher at pH 1 to 3, however, the chemical stability in solution is reduced so that a stable solution with a reasonable shelf-life cannot be achieved. In addition, the local tolerance of such a formulation is very poor. This is due to the fact that the target dose would require a drug concentration in solution which can only be achieved by a pH of about pH3 and lower. The required concentration in solution exceeds the solubility of pimobendan in water by a factor of about 250, a factor of 1 to 1000 might be the maximum required increase.
Certain etherified beta-cyclodextrin derivatives are known to improve solubility of sparingly soluble drugs (WO85/02767). However, in WO85/02767 only the use of etherified beta-cyclodextrin derivatives up to a concentration of 10% is described. A molar ratio of drug to etherified beta-cyclodextrin derivative of 1:6 to 4:1 was thought. The solubility of flubendazol within the above given ratio was only increased by a factor 30. However, those formulations are not suitable for the preparation of liquid preparations comprising pimobendan, or any other substituted benzimidazol in therapeutically effective amounts of up to 5 mg/ml, preferably of 0.5 to 3 mg/ml, even more preferably of 0.5 to 1.5 mg/ml. As mentioned above, at least pimobendan formulation comprising up to 1.5 mg/ml needs an increase in solubility at pH 7 by a factor of about 1000 to 1500.
The objective underlying the present invention was to provide liquid preparations comprising a substituted benzimidazol, preferably pimobendan as pharmaceutically active compound.
The objective underlying the present invention was to provide a pharmaceutically acceptable solution comprising a substituted benzimidazol, preferably pimobendan as pharmaceutically active compound.
Another objective underlying the present invention was to provide injectable solutions comprising a substituted benzimidazol, preferably pimobendan as pharmaceutically active compound.